Issue: May 2019
May 23, 2019
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Providers, regulators explore type 2 therapies for type 1 diabetes

Issue: May 2019
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For most children and adults with type 1 diabetes, day-to-day disease management remains difficult despite improvements in insulin formulations and delivery and advancements in diabetes technologies during the past decade.

Only 17% of children and 21% of adults with type 1 diabetes meet HbA1c targets outlined in American Diabetes Association guidelines, with glycemic control worsening over 8 years of follow-up among adolescents, in particular, according to an analysis of registry data.

DKA risk is already elevated for people with type 1 diabetes, and better education may be required for safe use of emerging therapies, according to Satish K. Garg, MD.

Photo by David Swaschnig. Printed with permission.

For many with diabetes, the biggest roadblock to better outcomes is a lack of noninjectable therapy options. Apart from pramlintide (Symlin, AstraZeneca), an injectable amylin analogue approved by the FDA in 2005, people with type 1 diabetes have no approved therapies to add to insulin to assist in attaining target blood glucose levels. Pramlintide, which is not approved in Europe, requires multiple daily injections in addition to insulin and is associated with an increased risk for severe hypoglycemia, as well as adverse events such as nausea and vomiting.

“Even with patient adoption of diabetes technology and newer insulins for blood glucose management, patients with type 1 diabetes struggle with tremendous and at times unpredictable variability in their glucose levels on a daily basis,” Carol J. Levy, MD, CDE, clinical director of the Mount Sinai Diabetes Center, told Endocrine Today. “Patients struggle with variable responses from an insulin injection for meals as well as confounding factors like exercise, stress, alcohol and many others, which impact daily glucose levels. We need to think about what other support we can provide for patients in addition to injectable treatments.”

Carol J. Levy

For the first time in more than a decade, noninsulin therapies specifically indicated for type 1 diabetes may be on the horizon, but questions loom regarding their safety and efficacy. In March, the FDA declined to approve oral sotagliflozin (Zynquista, Sanofi), a first-in-class dual SGLT1 and SGLT2 inhibitor for type 1 diabetes. The drug was approved in Europe in April. The FDA’s decision followed debate about an observed risk for diabetic ketoacidosis (DKA) — a problem that has kept already-approved type 2 agents out of reach for those with type 1 diabetes.

Still, such noninsulin options have been welcomed by diabetologists and patient advocates alike, who cite the continued poor outcomes for most children and adults with type 1 diabetes.

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“Unfortunately, DKA risk is increased in the background population itself, with or without therapy,” Satish K. Garg, MD, professor of medicine and pediatrics at the Barbara Davis Center for Diabetes, University of Colorado Denver, told Endocrine Today. “Down the road, I think sotagliflozin will ultimately get approved if Sanofi is able to adequately answer all of the questions in the complete response letter.”

Daniel Einhorn

Similar questions regarding the balance between benefits and risks with respect to DKA will likely arise with the SGLT2 inhibitor dapagliflozin (Farxiga, AstraZeneca), Garg said. In March, dapagliflozin became the first noninsulin agent for type 1 diabetes approved by the European Commission, and it is currently under FDA regulatory review as an adjunct to insulin in adults with type 1 diabetes. A decision is expected later this year.

“People are going to continue to use these drugs off-label,” Garg said. “Rather than do that, the FDA may as well approve them and have pharmaceutical companies partner in the education of patients and the providers. That is what should happen.”

Need for options

In January, the Endocrinologic and Metabolic Drugs Advisory Committee of the FDA split 8-8 in a vote to recommend approval of sotagliflozin. In discussion, committee members on both sides of the vote cited similar concerns about incidence of DKA observed across three phase 3 trials.

Several members also emphasized that people with type 1 diabetes have few options aside from titrating insulin dosing.

In a 2016 analysis published in The Lancet Diabetes & Endocrinology, Christian Seerup Frandsen, MD, a researcher in the department of endocrinology at Hvidovre Hospital and the University of Copenhagen, Denmark, and colleagues wrote that insulin therapy only partly addresses what they described as the paradoxical and pathophysiological excess of glucagon.

“In individuals with type 1 diabetes, the gastric emptying rate is altered, and even the most rapid-acting mealtime insulin peaks too late to match the postprandial glucose absorption, resulting in large postprandial glucose excursions,” Frandsen and colleagues wrote. “Intensive insulin treatment is associated with weight gain, adversely affecting the cardiovascular risk profile, and might reduce treatment compliance by patients missing insulin injections or reducing the dose, resulting in hyperglycemia.”

Several classes of agents indicated for type 2 diabetes, including GLP-1 receptor agonists, SGLT2 inhibitors and the alpha-glucosidase inhibitor acarbose, have been prescribed off-label in type 1 diabetes.

“When acarbose, the carbohydrate blocker, came out, we all tried it,” Daniel Einhorn, MD, FACE, FACP, clinical professor of medicine at the University of California, San Diego, told Endocrine Today. “It seemed clever, and it is. It is just not good enough. ... Most of the oral agents that we have require insulin to be useful. You can’t use most of the armamentarium if it’s an insulin-dependent mechanism. That’s just the nature of the disease.”

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Levy, who has type 1 diabetes, said it is difficult to develop additional agents that might be appropriate, aside from insulin-based medications.

“Type 1 diabetes is a somewhat different disease in that it is an insulin deficiency-related condition, and there aren’t other pathways [to target] that can be beneficial,” Levy said.

A complicating factor, according to experts, is a rising obesity prevalence among people with type 1 diabetes. According to 2015 data from the T1D Exchange Clinic Registry, nearly 40% of children and adolescents with the disease also have overweight or obesity — a rate that now mirrors the overall U.S. population.

“Today, we have a more overweight and obese type 1 generation vs. previous generations,” Osama Hamdy, MD, PhD, FACE, medical director of the Obesity Clinical Program at Joslin Diabetes Center and associate professor of medicine at Harvard Medical School, told Endocrine Today. “They are not only fighting type 1, they are fighting insulin resistance and the consequences of excess weight. These people need new therapy options and support tools that provide better feedback to move the needle in terms of outcomes.”

Osama Hamdy

Hamdy, who said he was surprised by the FDA’s decision to reject sotagliflozin, said he hopes the FDA reconsiders.

“This medication was a hope for many patients with type 1 diabetes who aim to reduce their insulin doses, have better diabetes control and lose some weight,” Hamdy said. “I hope the FDA doesn’t repeat the big mistake of metformin, when it was finally approved in December 1994 while being available everywhere else for decades, for the fear of lactic acidosis.”

Promise of SGLT inhibition

SGLT2 inhibitors, currently approved for type 2 diabetes, have shown promise in clinical studies for type 1 diabetes. These agents have been prescribed off-label in a small number of selected patients with type 1 diabetes, despite a small dose-dependent increased risk for DKA.

When prescribing these agent off-label, the patient must be fully informed and provide consent and should be monitored carefully for early signs of DKA, according to Helena W. Rodbard, MD, FACP, MACE, medical director of Endocrine and Metabolic Consultants in Rockville, Maryland, and a past president of the American Association of Clinical Endocrinologists and the American College of Endocrinology.

“When the class of SGLT2 inhibitors first became available, it was quickly embraced by endocrinologists,” Rodbard told Endocrine Today. “When major cardiovascular protective effects were demonstrated in large long-term cardiovascular outcomes trials, these drugs received even greater credence. Now that we know that SGLT2 and SGLT1 inhibitors can be safely used in type 1 diabetes if one uses appropriate mitigation strategies regarding DKA, we are even more enthusiastic.”

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In the DEPICT-1 study presented at the 2018 ADA Scientific Sessions, researchers assessed the efficacy and safety of 5-mg and 10-mg doses of dapagliflozin as an add-on to adjustable insulin in 833 patients with inadequately controlled type 1 diabetes (mean baseline HbA1c, 8.53%). At 24 weeks, patients in both dapagliflozin arms experienced mean HbA1c reductions of –0.42% and –0.45%, respectively, compared with those assigned placebo, as well as sustained weight loss and a reduction in insulin dose, without any associated increases in risks for hypoglycemia or DKA.

“SGLT2 inhibitors are the first class of antihyperglycemic drugs to show the potential for cardiovascular and renal benefit (even before manifestation of renal disease) in patients with type 2 diabetes,” the researchers wrote in The Lancet Diabetes & Endocrinology. “This effect might be partly related to a reduction in renal hyperfiltration, which is of particular importance in type 1 diabetes, especially considering the younger age of presentation compared with type 2 diabetes.”

Following similar studies, the European Medicines Agency’s human medicines committee in January recommended extending the indication of dapagliflozin to patients with type 1 diabetes and a BMI of at least 27 kg/m², when insulin alone does not provide adequate glycemic control. The committee’s opinion was forwarded to the European Commission, which approved an EU-wide marketing authorization in March.

Rodbard, who has prescribed SGLT2 inhibitors off-label for more than 100 patients with type 1 diabetes, said most of them experienced improved glycemic control and quality of life with the therapy. An option specifically indicated for type 1 diabetes, she said, would be welcome.

Sotagliflozin works differently from an SGLT2 inhibitor, which prevents the kidneys from reabsorbing glucose back into the blood. Instead, sotagliflozin inhibits both the SGLT1 and SGLT2 proteins responsible for glucose regulation, blunting and delaying the rise in glucose after meals by reducing glucose absorption in the proximal intestine.

Benefit vs. risk

As with SGLT2 inhibitors, DKA was the most concerning adverse reaction associated with the dual SGLT1 and SGLT2 inhibitor sotagliflozin, according to the FDA committee. In agency analyses, sotagliflozin was associated with an approximately eightfold increase in DKA risk vs. placebo (95% CI, 3.1-19.9). The estimated number needed to harm was approximately 26 patient-years of exposure to sotagliflozin to observe one additional DKA event, according to the FDA (95% CI, 20.1-38.5).

At the time, committee members called for a risk evaluation and mitigation strategy if the FDA were to move forward with the drug.

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“I did not see clear evidence that the benefit outweighs the risk [for DKA] here,” Michael Blaha, MD, MPH, assistant professor of cardiology and epidemiology and director of clinical research at the Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, said following his “no” vote during the meeting. “And this is in a clinical trial setting with exquisite follow-up of these patients. I appreciate the anecdotes that we heard during public comment [suggesting benefit] ... but we didn’t get to hear from people who had DKA, and their life might have changed from that potentially life-threatening outcome.”

Additionally, subgroup analyses showed a consistently elevated DKA risk associated with sotagliflozin, with estimated hazard ratios ranging from 4 to 11.

“I personally have had patients with type 2 and type 1 using an SGLT2 inhibitor go into euglycemic DKA — I have seen it,” Einhorn said. “First of all, they do fine. What is remarkable is they want to go right back on the drug, the moment they are well ... because they experience smoother control, and that feels better. I think freedom from the idea of being tethered to the exact number of units of insulin to give for breakfast is liberating. Those of us who don’t live with type 1 do not fully realize that this is a minute-to-minute disease.”

In a 2018 meta-analysis, researchers found that combined treatment with SGLT2 inhibitors and insulin is a viable option for treating patients with type 1 diabetes. In an analysis of four randomized controlled trials of therapy with SGLT2 inhibitors, including dapagliflozin, researchers found that SGLT2 inhibitors lowered HbA1c and were associated with lower daily doses of insulin and lower body weight compared with placebo. However, the researchers acknowledged that the study was limited by its small sample size, as three of the four trials included fewer than 100 participants. Furthermore, the studies included in the analysis used varying lengths of treatment, including two that ran for less than 12 weeks.

Einhorn, who said the amount of DKA observed in the sotagliflozin studies was not unreasonable, said patient and provider education is key.

“What gets people into trouble is the glucose signal for DKA might not be there,” Einhorn said. “Because of the way SGLT2 inhibitors work, a patient’s blood sugar may look pretty good, even though the person is in DKA.”

In February, Diabetes Care published an international consensus statement on risk management of DKA in patients with type 1 diabetes treated with SGLT inhibitors. The report, which followed a June 2018 consensus conference on the topic, outlined several recommendations for patients prescribed agents in the class, including initiating therapy at the lowest dose possible, regular ketone monitoring, either via lab or home testing, and a “cautious” reduction in insulin dose.

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“The debate in this committee centered around when ketones should be checked,” said Rodbard, a co-author of the consensus statement. “We really didn’t come up with any conclusions except that all of us have personal preferences. I tell my patients to check ketones irrespective of blood glucose levels. The majority of DKA cases had blood glucose levels less than 250 mg/dL — not exactly euglycemic, but a slight elevation that you would not expect in typical DKA. The level of awareness should be increased.”

Einhorn said any approval of an SGLT-inhibiting agent for type 1 diabetes will likely hinge on creating an effective mitigation program that will educate patients and providers.

Helena W. Rodbard

“We’ll have to come up with some fundamental way of staying in touch with patients, at least for the first year or two, once they are prescribed the therapy,” Einhorn said. “This has to happen. If a drug improves quality of life, patients want it. It’s happening off-label right now.”

‘A technology question’

In an analysis of T1D Exchange survey data from 2016 to 2018, researchers noted that 3% of more than 22,000 registrants reported experiencing at least one DKA event in the 3 months before the questionnaire, with the highest frequency (4%) in participants aged 26 years and younger.

Participants using continuous glucose monitoring had fewer DKA events than non-CGM users, according to the report, and participants with a higher HbA1c were more likely to experience a DKA event vs. participants with lower HbA1c.

Levy said better use of technology, including CGM and sensor therapy, combined with patient education, could help mitigate the risks associated with an agent like sotagliflozin.

“It becomes a technology question,” Levy said. “Technology provides a significant benefit for patients with type 1, if they feel comfortable adopting it. That does not just mean using an artificial pancreas system. It means increased decision support for patients who choose not to use closed-loop systems.”

Levy, who called the FDA’s decision on sotagliflozin disappointing, said it is critical that people with type 1 diabetes have new therapy options. A future approval of the drug could potentially pave the way for expanded indications for SGLT2 inhibitors used in type 2 diabetes.

“There are several other drugs of a similar nature within this class that have the opportunity to get approved,” Levy said. “We need to be cautious that, as we move forward, we do this in a thoughtful way from a product approval standpoint. We must make sure the FDA is aware of the importance of this agent for patients and of how to address factors aside from HbA1c reduction that can be important to patients. It is not just about HbA1c. It is about quality of life.” – by Regina Schaffer

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Disclosures: Einhorn reports he has served as a consultant for Sanofi. Garg reports he has served on advisory boards for Dexcom, Eli Lilly, Lexicon, Mannkind, Medtronic, Merck, Roche and Sanofi, and received research grants through his institution from Animas, Dario, Dexcom, Eli Lilly, JDRF, Lexicon, Medtronic, Merck, NIDDK, Novo Nordisk, Sanofi and T1D Exchange. Hamdy reports he serves on advisory committees for AstraZeneca and Sanofi Aventis, is a consultant for Abbott Nutrition and Merck, and is a shareholder for Healthimation LLC. Levy reports she has received advisory fees from Sanofi. Rodbard reports she has received grant support and consultant fees from AstraZeneca, Boehringer Ingelheim, Janssen, Lexicon, Lilly, Novo Nordisk and Sanofi.

Click here to read the POINTCOUNTER, "Is insulin pump therapy superior to multiple daily injections in type 1 diabetes?"